Editorial

Beijing, an incredible city, was the site for the 4th International Forum on Rheumatoid
Arthritis (IFRA), an incredible meeting. Professor Zhan-guo Li, Professor of Medicine
at Peking University and President of the Asia Pacific League Against Rheumatism,
and his co-chairs, Professor Lars Klareskog, Professor of Rheumatology, Karolinska
Institutet, and Professor Kazuhiko Yamamoto, Professor of Medicine, University of
Tokyo, organized the meeting. They did a terrific job and created a program to showcase
the excitement and dynamism of both modern China and modern rheumatology. Professor
Li was a great host as hundreds of Chinese rheumatologists packed the Beijing Xinyuan
Hotel to hear lectures by rheumatologists from China as well as invited speakers from
around the world. I have attended few meetings where the energy was so high and the
eagerness to learn so great.

While most of the international speakers had previously visited Beijing, the meeting
was my first trip to China. To say the least, I was surprised by the city's modernity.
Growing up in a very frosty time of the Cold War, China - usually called Red China
or Communist China in the United States - was very much a forbidden country until
Nixon thawed relationships with secret diplomacy, a ping-pong tournament and a memorable
visit in 1972. I remain uncertain about the city's name because, during my lifetime,
Beijing has also been called both Peking and Peiping. The images I have of modern
China come mostly from the telecasts of the 2008 Olympics, although the NBC commentators
seemed mostly interested in street food as if restaurants did not exist. I had few
preconceived ideas of the real Beijing as opposed to the attractions I read about
in 1000 Places to See Before You Die.

While China is a very old country, Beijing is a very new city. I would say that Beijing
has the ambience of a boom town - but boom town is a misnomer for a megalopolis that
has a population of about 20 million people and a land area of 6,500 square miles.
About half the size of Belgium, Beijing makes Chicago look like a quaint little village
with its neighborhoods of row houses. High-rise apartments and office buildings are
everywhere as if the only direction to grow is up. Alas, a dense haze often covers
the landscape, blotting the outline of some beautiful buildings and preventing appreciation
of the sheer magnitude of the construction that has marked the explosive growth of
Beijing in recent years.

Throughout the city, wide avenues and highways are dense with cars at all hours. Driving
around for sightseeing, I was gratified (and indeed mystified) to see many cars with
Buick on the name plate. Indeed, I probably saw more Buicks in Beijing than I do in
Durham, North Carolina. There used to be an advert that said 'This is not your father's
Buick.' I guess in China the advert says 'This is not your American's Buick.' That
would be true since the car is the product of GM Shanghai, a joint venture of General
Motors and CDAI. Actually, GM sells more cars in China than in the United States.
Volkswagens, Hyundais and Audi are also frequent vehicles and far outnumber the bicycles
and scooters I was expecting.

As a tourist attraction, the ultra-modern Birds Nest Olympics stadium with its gleaming
lattice shell designed by Swiss architects now competes for attention with the ancient
Great Wall, the Forbidden City and the Summer Palace. The Egg is another landmark
and a great building. For those who delight in stirring architecture, I recommend
Beijing Airport. Airports are not usual venues for sightseers since they call forth
memories of long lines at immigration, canceled flights and lost luggage. Nevertheless,
Beijing Airport is a spectacular structure that is filled with light from an undulating
ceiling of windows. The outside roof is painted red, the Chinese symbol for good luck.
If you go to Beijing, you of course visit the airport, perhaps discombobulated by
the time-zone change. My recommendation is to rouse yourself awake and look at the
building and not just stumble through it.

Like China, rheumatology research is experiencing a boom and is on the go. As talks
at the IFRA demonstrated clearly, modern science moves with incredible speed and is
producing voluminous data at a dizzying pace. The technology keeps getting better
and better, the analysis of the pathogenesis more and more precise. (Alas, while I
saw the data presented by speakers from China, I will have to confine my comments
to those talks that were in English. I want to make sure that my comments are reasonably
correct and apologize to those whose work I cannot describe with confidence.)

Still in the midst of the genetics revolution, rheumatology is entering the epigenetics
revolution. Studies by Professor Steffen Gay of Zurich and Professor Gary Firestein
of San Diego described extraordinary progress in unraveling epigenetic changes in
fibroblasts that may endow these cells with an invasive phenotype. These changes can
result from base methylation reactions that lead to long-term changes in gene function;
interestingly, some epigenetic changes may be transmitted through the generations.
In this talk, Professor Gay raised the possibility of therapies to undo epigenetic
modifications, including some agents that I can purchase at my local GNC store. Discussing
another element of gene regulation, Professor Iain McInness of Glasgow illustrated
how miRNA can regulate key events in immune activation. miRNA can be a target for
therapy, as illustrated by findings from Professor Gay and colleagues on the use of
antagomirs in a pulmonary hypertension model.

Modern technology is also providing new insights into B-cell abnormalities that underpin
autoimmunity in rheumatoid arthritis (RA). Presenting a study of antibodies to citrullinated
proteins (ACPA), Professor Klareskog described the extraordinary commitment of synovial
B cells to ACPA production, with about 30% of these cells pumping out immunoglobulin
to drive events in synovial inflammation. ACPA may have some unexpected roles in pathogenesis
since, as Professor Klareskog showed, antibodies to citrullinated vimentin may trigger
osteoclastogenesis, perhaps driving bone loss that is so characteristic of RA. Complementing
these talks was a presentation by Professor Joachim Kalden of Erlangen on the treatment
of autoimmunity with bortezemib, a proteasome inhibitor that can interfere with plasma
cells. In both murine models as well as early studies on patients with lupus, this
agent can reduce anti-DNA levels; effects on protective antibodies are of course a
concern and will be closely watched as this therapy advances.

A presentation by Professor Ed Keystone of Toronto illustrated striking progress on
the clinical front. Professor Keystone addressed two main topics, highlighting recent
presentations from the European League Against Rheumatism meeting in Berlin. Two messages
are clear. The first is that, in head-to-head trials, agents that differ in action
can lead to similar clinical responses. Adalimumab and subcutaneous abatacept thus
showed comparable efficacy; reference to prior trials suggests that the effects of
subcutaneous abatacept may differ from those of the intravenous formulation with respect
to the time course and magnitude of the response. The results of the head-to-head
trials are also surprising in view of an impression that the efficacy of co-stimulatory
blockade may differ from that of TNF blockade. These studies raise the question of
why agents that attack fundamentally different cellular pathways act so similarly.
While current terminology emphasizes the concept of targeted therapy, the action of
treatments may converge so that the same bull's eye is hit even if the arrows come
from different directions.

A second message of Professor Keystone's talks relates to remission. As the data he
presented showed, treatment of RA with current agents and strategies (that is, treat
to target and tight control) can induce remission in a significant number of patients
as defined by well-established outcome measures. Furthermore, as he reported in patients
achieving remission with a combination approach, elimination of a biological agent
does not lead to relapse in many patients, with remission sustained at least over
months. In the words of Professor Keystone, this is a game changer.

I think that the frequency of remission in recent clinical studies has caught many
rheumatologists off guard. RA has long been conceptualized as a chronic, even relentless,
disease with changes (?epigenetic) in synoviocytes leading to joint destruction even
in the absence of inflammation. Interpretation of these clinical studies is, of course,
dependent on the definition of remission and the extent of subclinical synovitis and
radiological progression that may occur in a patient in whom arthritis seems quiescent.

Outcomes researchers will have ample opportunity to debate the criteria for remission
and which composite measures (Disease Activity Score, Clinical Disease Activity Index,
Simplified Disease Activity Index, Boolean), and their components, are most informative
and reliable. I sometimes think rheumatologists do not really know how to quantify
disease activity, for either clinical or research purposes, especially when inflammation
is low. In my own clinical practice, I have thought that joint tenderness is important
to this determination although Professor Keystone, an expert with decades of experience,
gave the nod to joint swelling as a measure of active disease. During a discussion
session, I asked Professor Keystone about his approach to assess swelling. He said
ballottement of joint swelling is key, showing how he squeezes a joint with his fingers
to determine its character and the presence of inflammation. If rheumatologists have
to rely on ballottement to make crucial decisions to start or stop drugs, I have my
concerns. Given the power and elegance of today's science, some biomarker or imaging
modality must be out there to help with decision-making and tell whether the fire
of inflammation smolders or has been successfully doused.

In addition to its importance clinically, the phenomenon of remission should drive
inquiry into disease mechanisms, providing a unique setting to explore critical events
in pathogenesis. Much research in rheumatology now focuses on preclinical autoimmunity,
the time prior to the onset of clinical symptoms, in which immune cell abnormalities
(for example, ACPA expression, cytokine production) are revving up for their full
onslaught. With remission, there is perhaps now a state of postclinical autoimmunity
in which signs and symptoms abate.

What is going on in patients with remission? Consider two examples. ACPA have a close
relationship to RA, with some data, including animal studies, pointing to a direct
role in joint inflammation. If ACPA titers do not change much during remission, then
their role in pathogenesis is up for grabs. Perhaps during remission, ACPA specificity
shifts in some subtle but significant way to nonpathogenic species. Since these antibodies
emanate from long-lived plasma cells, however, I doubt such a change. Alternatively,
an antigen required for immune complex formation may have disappeared during remission
or, more probably, the downstream effectors have been quieted.

A second example relates to epigenetics. Many current studies on the epigenetic modification
of fibroblasts involve operative specimens obtained at the time of replacement joint
surgery. Synoviocytes in such tissues have been subject to years (?decades) of inflammation,
the assault of biomechanical stress and even a slug or two of intra-articular glucocorticoids
to go along with years of disease-modifying antirheumatic drugs. Until the advent
of remission, it would be difficult to know which of these changes is primary or secondary
- although, as Dr Firestein showed, IL-1 can affect DNA methylation. Now, with remission,
epigenetic imprinting can be studied in a new way, although obtaining samples of synovium
during remission may be challenging unless techniques for easy tissue retrieval become
available.

The IFRA occurred in the midst of the US presidential election although, with current
politics, it seems we are always in the midst of a presidential election. Talk of
2016 is already heating up. Palin versus Clinton? Whatever the outcome of the 2012
contest - red or blue - the prospects for the National Institutes of Health budget
look bleak - gray if not black. Given the drive to shrink the federal budget and blot
away red ink, stagnant funding may be the best we can do although genuine cutbacks
may occur. Cutbacks on research now would be a great tragedy since technology is leading
to unprecedented discoveries that can be translated into treatment advance. I wish
some of our politicians would have attended the IFRA to hear lectures by Chinese investigators
or to speak to Chinese students whose numbers have swelled with the influx of government
money. Those politicians would have seen what a commitment to building research can
accomplish in terms of innovation, economic growth and the inspiration provided to
young people who are anxious to discuss the effects of IL-2 on regulatory T cells
or the role of STING in the immune response to DNA in lupus.

According to de Tocqueville, the genius of America came from the pursuit of 'self-interest
properly understood.' China seems to be taking a different path, however. Practically
and philosophically, it seems that China wants to pursue national interest properly
understood. In either system, proper understanding must balance the interests of the
individual and those of the state, always a great challenge. China is an old country
and America is a young one, but both are struggling to find a balance consistent with
their histories and cultures. Given the importance of US and Chinese economies in
the world, there will be many onlookers to this great political process.

I was honored to attend the IFRA and witness the extraordinary accomplishments of
China in rheumatology research. It was a truly wonderful occasion of fellowship and
cooperation, and I was excited to meet and toast new friends with potently delicious
Chinese wine that had a strong resemblance to what in North Carolina we call white
lightning. I look forward to many more years of international cooperation as we work
together to advance rheumatology research and improve the health of people of the
world properly understood.